Process of preparing 3-phenyl-quinoline-5-carboxylic acid

ABSTRACT

A process for preparing 3-phenyl-quinoline-5-carboxylic acid comprising reacting 4-amino-3-hydroxyphthalide with phenylacetaldehyde.

This is a division, of application Ser. No. 07/757,865, filed Sep. 11,1991 now U.S. Pat. No. 5,210,231.

The present invention relates to 4-amino-3-hydroxyphthalide, animportant intermediate for the synthesis of3-substituted-5-quinoline-carboxylic acids and to a process for itspreparation.

3-Hydroxyphthalides which are substituted in the phenyl ring, optionallypolysubstituted, by chlorine, carboxyl or methoxy, are known from thepublications J. Org. Chem. 1988, 53, 223-224; 53, 1199-1202 and J. ofMed. Chem., 1988, Vol. 31, No. 4, 824-830.

The present invention relates to the new compound4-amino-3-hydroxyphthalide of the formula (I). ##STR1##

The invention furthermore relates to a process for the preparation ofthe compound of the formula (I), characterised in that

4-Nitro-3-hydroxyphthalide of the formula (II) ##STR2## is reduced ininert solvents, preferably by hydrogenation, in the presence of acatalyst.

The process can be illustrated by the following equation: ##STR3##

Suitable solvents for the hydrogenation are all organic solvents whichdo not change under the reaction conditions. These preferably includealcohols such as methanol, ethanol, propanol or isopropanol, or etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether,or diethylene glycol dimethyl ether or amides such ashexamethylphosphorous triamide or dimethylformamide, or acetic acid andmethylene chloride, carbon tetrachloride or toluene. It is also possibleto use mixtures of the solvents mentioned. Methanol, ethanol, propanolor tetrahydrofuran are preferred.

The hydrogenation can be carried out at normal pressure or at elevatedpressure, for example from 0.5 to 5 bar, preferably at atmosphericpressure.

The reduction is in general carried out in a temperature range from O°C. to 80° C., in the case of hydrogenation preferably at roomtemperature.

Suitable catalysts are platinum, palladium, palladium/animal charcoal,palladium/barium sulphate or Raney nickel. Palladium/barium sulphate isparticularly suitable.

The catalyst is employed in an amount from 0.00001 to 1 mol, preferablyfrom 0.001 to 0.1 mol, relative to 1 mol of the compound of the formula(II).

The compounds of the formula (II) are known [cf. T. Watanabe et al.,Chem. Pharm. Bull, 20 (10), 2123-2127 (1972)].

The above preparation process is only given for clarification. Thepreparation of the compound of the formula (I) according to theinvention is not restricted to this process, but any modifications ofthis process, for example the use of nitro-amino reduction methods knownfrom the literature, are utilisable in the same manner for thepreparation of the compound according to the invention.

The compound according to the invention is a useful intermediate for thedirect preparation of 3-substituted quinoline-5-carboxylic acids, whichare known in some cases or are new, which are used in turn as startingsubstances for the corresponding 3-substituted quinoline-5-aldehydes andare thus of great importance in 1,4dihydropyridine chemistry.

PREPARATION EXAMPLES Example 1 4-Amino-3-hydroxyphthalide ##STR4##

10 g of 3-hydroxy-4-nitro-phthalide are dissolved in 100 ml oftetrahydrofuran and, after addition of 1 g of palladium on bariumsulphate (5%), the mixture is hydrogenated at atmospheric pressure and20°-25° C. The catalyst is filtered off and the filtrate isconcentrated. The evaporation residue is stirred with ether and filteredoff with suction. 5.8 g (68.5% of theory) of a colourless substance ofmelting point 280°-285° C. (dec.) are obtained.

EXAMPLE 2 3-Phenyl-Quinoline-5-Carboxylic Acid ##STR5##

50 g (0.256 mol) of 3-hydroxy-4-nitro-phthalide are hydrogenated at 20°C. and 3 bar in 380 ml of ethanol using 5 g of palladium/barium sulphate(5%). The catalyst is filtered off with suction, and 0.308 mol (38.7 ml)of phenylacetaldehyde is added to the filtrate. The mixture is boiledfor 4 hours, the quinolinecarboxylic acid precipitating. It is cooled,filtered off with suction and washed with ethanol. 28.3 g (44.3% oftheory) of a colourless compound of melting point>290° C. are obtained.

I claim:
 1. A process for preparing 3-phenyl-quinoline-5-carboxylic acidhaving the formula ##STR6## comprising reacting4-amino-3-hydroxy-phthalide of the formula ##STR7## withphenylacetaldehyde.